Colon cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women in the United States. Even among colon cancer patients who are apparently diagnosed early (Dukes'B/stage II), roughly half relapse after resection, suggesting that many colorectal cancers metastasize early. Despite this high incidence of relapse, the use of adjuvant chemotherapy in stage II colon cancer is controversial, primarily because it is not currently possible to discriminate patients for whom such therapy is clearly warranted. A need therefore exists for establishing predictive markers that identify patients deserving of adjuvant chemotherapy. In addition to early stage disease, among patients with more advanced disease (stage III/Dukes'C), adjuvant chemotherapy is routinely administered, but not all stage III patients benefit. Thus, a need exists to identify which stage III patients are deserving of alternative, perhaps more aggressive adjuvant regimens. Defects in cell lifespan regulation, particularly apoptosis, constitute one of the six recognized cardinal characteristics of cancers. This proposal focuses on changes in expression of apoptosis-regulating proteins in colon cancers and seeks to test the hypothesis that apoptosis biomarkers can serve as highly predictive indicators of clinical outcome for patients with either Stage II or III colorectal cancer. By taking advantage of the rich resources of a large tumor bank managed by a network of hospitals, and using tissue microarray (TMA) technology for rapidly analyzing large numbers of archival tumor specimens from uniformly treated patients for whom extensive follow data already exist, we propose to profile by quantitative immunohistochemistry methods (employing digital image analysis scoring algorithms) the expression of specific apoptosis-regulating proteins for which we have previously obtained evidence of predictive significance. The proposed retrospective correlative analysis of apoptosis biomarkers and patient outcome is aimed at validating biomarkers of predictive value. Altogether, these studies will establish predictive biomarkers that help to discriminate indolent from aggressive colon cancers, thus setting the stage for future prospective studies that confirm the predictive significance of these biomarkers, thereby providing a rational means to the personalization of therapeutic strategies for patients with colon cancer. PUBLIC HEALTH RELEVANCE: Colon cancer is a leading cause of death, yet treatment for this malignancy remains empirical. Some patients are over-treated for fear of metastatic spread that has not actually occurred while others are under-treated with "gentle" chemotherapy that fails to eradicate tumor cells. The proposal seeks to provide diagnostic test that will distinguish indolent from aggressive colon cancers and thus guide rational and personalized treatment approaches for patients.